Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastases). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
Pre-malignant abnormal cell growth is exemplified by hyperplasia, metaplasia, or most particularly, dysplasia (for review of such abnormal growth conditions, see Robbins & Angell, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68-79) The neoplastic lesion may evolve clonally and develop an increasing capacity for growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance (Roitt, I., Brostoff, J. and Kale, D., 1993, Immunology, 3rd ed., Mosby, St. Louis, pps. 17.1-17.12). The epidemiology of cancer in the United States is estimated at greater than 1,300,000 new cases and greater than 550,000 deaths (Jemal et al., 2003, CA Cancer J. Clin., 53, 5-26) estimated for 2003. Lung cancer is one of the most common cancers with an estimated 172,000 new cases projected for 2003 and 157,000 deaths in the US (Jemal et al., 2003, CA Cancer J. Clin., 53, 5-26). Lung carcinomas are typically classified as either small cell lung carcinomas (SCLC) or non-small cell lung carcinomas (NSCLC). SCLC comprises about 20% of all lung cancers with NSCLC comprising the remaining approximately 80%. NSCLC is further divided into adenocarcinoma (AC) (about 30-35% of all cases), squamous cell carcinoma (SCC) (about 30% of all cases) and large cell carcinoma (LCC) (about 10% of all cases). Additional NSCLC subtypes, not as clearly defined in the literature, include adenosquamous cell carcinoma (ASCC), and bronchioalveolar carcinoma (BAC).
Lung cancer is the leading cause of cancer deaths worldwide, and more specifically NSCLC accounts for approximately 80% of all disease cases (Cancer Facts and Figures, 2002, American Cancer Society, Atlanta, p. 11.). There are four major types of NSCLC, including adenocarcinoma, squamous cell carcinoma, bronchioalveolar carcinoma, and large cell carcinoma. Adenocarcinoma and squamous cell carcinoma are the most common types of NSCLC based on cellular morphology (Travis et al., 1996, Lung Cancer Principles and Practice, Lippincott-Raven, New York, pps. 361-395). Adenocarcinomas are characterized by a more peripheral location in the lung and often have a mutation in the K-ras oncogene (Gazdar et al., 1994, Anticancer Res. 14:261-267). Squamous cell carcinomas are typically more centrally located and frequently carry p53 gene mutations (Niklinska et al., 2001, Folia Histochem. Cytobiol. 39:147-148).
Lung carcinoma is the number one killer amongst cancer patients, for which no adequate treatment exists, corresponding to about one-fifth of all cancer deaths in Europe (IARC). The growing burden on the population is probably best illustrated from recent studies in the US, showing that between 1960 and 1990, deaths from lung cancer among woman increased over 400% in the period to exceed breast cancer deaths.
Currently no adequate treatment protocols for the different types of lung cancer exist. With conventional therapy, median survival for the subtype of SCLC is 15 months for limited-stage disease and 9 months for extensive-stage disease, whereas long-term survival is very low.
Major obstacles to the successful treatment and eradication of lung cancer are late diagnosis, highly metastatic behaviour, resistance to chemotherapy and the impossibility to surgically remove all cancer cells. In principle, cancer vaccines are a most promising approach for the treatment of cancer in general and lung cancer in particular. Major obstacles in the development of a successful vaccine are the lack of cancer specific antigens to be targeted and the lack of tools to evaluate immunotherapy based on such targets. An additional problem is the above cited heterogeneity of lung cancer.
In contrast to many other types of cancer, lung cancer treatment has not resulted in significant improvements in survival rates during the last decades, showing an overall 5-year survival of only 14% (Haura EB.2001, Cancer Control; 8: 326-336); Crawford J. (medscape, article 429347_1, published Mar. 01, 2002). To date the decision upon treatment protocols is especially guided by the subdivision into SCLC and NSCLC. Unlike the other types of lung cancer, SCLC is sensitive to chemotherapy. In about 75% of the cases of SCLC an initial response to chemotherapy can be noticed, with a clinically complete response in about 35% of all cases (Johnson D H, et al., 1987; Am J Med Sci 293: 377-389). Unfortunately, however, in most cases relapse occurs, resulting in a three year survival rate of only 5-10%, and a five-year survival rate of about 1% (Minna J D,et al. 1985, Cancer of the lung. In: Cancer. Principles and practice of oncology 2nd ed); Within SCLC a clinically relevant subdivision can be made between classic and variant SCLC. The variant-type of SCLC appears to be even less sensitive to chemotherapy and radiotherapy. As a result the median survival time of patients suffering from the variant-type of SCLC is significantly shorter than of those with a classic type of SCLC (Radice PA, et al. 1982, Cancer; 50: 2894-2902). Also for patients with a combined SCLC a poorer prognosis than for patients with classic SCLC is observed (Hirsch FR et al, 1983, Cancer; 52: 2144-2150). Approximately 75% to 80% of cases are of the NSCLC histology, and the majority of patients present with either locally advanced disease (stage III) or metastatic disease (stage IV). Importantly, patients undergoing curative surgical resection for apparent localized disease have survival rates ranging between 50% and 80%, implying the need for better systemic treatment to cure occult micrometastatic disease. In NSCLC treatment with chemotherapy is in general unsuccessful (Minna J D, et al. 1985, Cancer of the lung. In: Cancer. Principles and practice of oncology 2nd ed.). Therefore, with the exception of high cure rates for surgical treatment of truly localized disease, the prognosis for patients with NSCLC is grim (Mulshine J L,et al. 1986., J Clin Oncol; 4: 1704-1715). In a small subset of patients, however, a response to chemotherapy can be observed. In part, these cases might represent NSCLC in which SCLC-components occur since such a heterogeneous composition is quite common in lung cancer (see above) It may be obvious from these data that alternative treatment modalities for these patients are critical.
The main objective of the present invention is the development of a new model for the biology and antigenicity of lung cancer and developing a new concept for a lung cancer vaccination therapy. The approach will be directed towards target discovery—antigens specific for SCLC and NSCLC and immunization strategies.
A number of tumor-associated antigens have been identified in human lung cancers and are being used as targets for general lung cancer vaccines. These include the carcinoembryonic antigen (CEA), human epithelial mucin MUC-1, the cancer-testis antigen NY-ESO-1, and the ganglioside Fuc-GM1 (Haura E B. 2001, Cancer Control, 8: 326-336; www.medscape.com/viewarticle/409059). Vaccination of tumor patients with inactivated tumor cells has been tried decades ago with not much success. The intra-tumoral injection of heat-killed Mycobacteria into SCLC lesions as an adjuvant with autologous tumor cells has led to some success.
NSCLC can evoke specific humoral and cellular antitumor immune responses in some patients (Salgia R, et al. 2003; J clin Oncol; 21:624-630.). Serology-based cloning strategies have identified multiple tumor-associated antigens, including eIF4G, aldolase, annexin XI, Rip-1, and NY-LU-12. Humoral responses to autologous lung cancer cells may be associated with prolonged survival. T-cell-based cloning strategies similarly have revealed diverse targets in NSCLC, including Her2/neu, SART-1, SART-2, KIAA0156, ART-1, ART-4, cyclophilin B, mutated elongation factor 2, malic enzyme, and alpha-actinin-4. The development of cytotoxic T-lymphocyte responses to NSCLC may also be correlated with prolonged survival.
In clinical practice, accurate diagnosis of various subtypes of cancer is important because treatment options, prognosis, and the likelihood of therapeutic response all vary broadly depending on the diagnosis. Accurate prognosis, or determination of distant metastasis-free survival could allow an oncologist to tailor the administration of adjuvant chemotherapy, with patients having poorer prognoses being given more aggressive treatment. Furthermore, accurate prediction of poor prognosis would greatly impact clinical trials for new lung cancer therapies, because potential study patients could then be stratified according to prognosis. Trials could be limited to patients having poor prognosis, in turn making it easier to discern if an experimental therapy is efficacious. To date, no set of satisfactory predictors for prognosis based on the clinical information alone has been identified.
It would, therefore, be beneficial to provide specific methods and reagents for the diagnosis, staging, prognosis, monitoring and treatment of cancer, including lung cancer. It would also be beneficial to provide methods that identify individuals with a predisposition for the onset of lung cancer, and other types of cancer, and hence are appropriate subjects for preventive therapy.